Certain substituted cyclohexyl ureas and thioureas

ABSTRACT

1-(4-Higher alkyl-substituted cyclohexyl)-3-alkyl and 3,3dialkylureas and thioureas of the formula: WHEREIN R is alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl or tricycloalkyl; R1 and R2 are hydrogen, alkyl, haloalkyl, cyanoalkyl, nitroalkyl, alkoxyalkyl, thioalkoxyalkyl, and A is oxygen or sulfur. Typical is 1-(cis-4-cyclohexylmethylcyclohexyl)-3-methylurea useful as an animal repellant.

United States Patent Knowles 1451 Aug. 22, 1972 1 CERTAIN SUBSTITUTED2,653,169 9/1953 Hurwitz ..260/561 CYCLOHEXYL UREAS AND 2,551,378 5/1951 Kirby ..260/553 THIOUREAS 2,661,272 12/1953 Searle ..71/1 193,000,940 9/ 1961 Raasch ..260/ 553 [721 m g Kmwles, "ockessm 3,006,99510/1961 Steinbrunn et a1. l78/7.2

[73] Assignee: E. I. du Pont de Nemours and Com- Primary Examner-LfilandSebastian pany, Wilmington, Del. Attorney-Herbert W. Larson [22] Filed:April 20, 1967 57 ABSTRACT PP 635,301 1-(4-Higher alkyl-substitutedcyclohexyl)-3-alkyl and Related US. Application Data Continuation-impartof Ser. No. 574,498, Aug. 18, 1966.

References Cited UNITED STATES PATENTS 9/1961 Fischer et al. ..71/1193,3-dialkylureas and thioureas of the formula:

R is alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl or tricycloalkyl;R and R are hydrogen, alkyl, haloalkyl, cyanoalkyl, nitroalkyl,alkoxyalkyl, thioalkoxyalkyl, and A is oxygen or sulfur. Typical is1-(cis-4-cyclohexylmethylcyclohexyl)-3- methylurea useful as an animalrepellant.

8 Claims, No Drawings CERTAIN SUBSTITUTED CYCLOHEXYL UREAS ANDTI-IIOUREAS CROSS REFERENCE This application is a continuation-in-partof my application Ser. No. 574,498, filed Aug. 18, 1966.

BACKGROUND OF THE INVENTION US. Pat. application Ser. No. 532,544, filedMar. 1, 1966, now abandoned, discloses compounds containing cyclohexylring structures having utility as animal repellants. I have nowdiscovered another class of compounds containing a cyclohexyl ringstructure which also has utility as animal repellants.

SUMMARY OF THE INVENTION This invention relates to substitutedcyclohexylureas.

More specifically this invention refers to I-(4-higher alkyl substitutedcyclohexyl)-3-alkyl and3,3-dialkylureas and thioureas, compositionscontaining them and methods of applying them to animals.

Potent animal inhalation irritant effects are achieved by applying toanimals or their habitat, compounds of the formula:

A B1 H H RC NCN wherein R is alkyl of three through eight carbon atoms,cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of fivethrough carbon atoms, bicycloalkyl of seven through 10 carbon atoms, andtricycloalkyl of 10 through 1 1 carbon atoms;

R and R can be the same or different and are hydrogen, alkyl of onethrough four carbon atoms, haloalkyl of one through four carbon atoms,cyanoalkyl of one through four carbon atoms, nitroalkyl of one throughfour carbon atoms, alkoxyalkyl where the alkoxy is one through four andthe alkyl is one through four carbon atoms and thioalkoxyalkyl where thethioalkoxy is one through four and the alkyl is one through four carbonatoms;

A is oxygen or sulfur.

Substitutions on the cyclohexyl ring must be in the cis configuration toobtain optimum irritant efiects.

Most preferred because of high irritant effects at a low use rate isl-(cis-4-cyclohexylmethylcyclohexyl)-3- methylurea.

UTILITY Compounds of this invention cause potent irritation to animaltissue, particularly to the mucous membranes.

Animals exposed to the above compounds show signs of severe respiratoryirritation and are quickly incapacitated. These compounds have twoadvatnages over currently used riot control agents such as 2-chloroacetophenone (CN), and animal repellants such asallylisothiocyanate for dogs and bone tar oil for deer. One, thecompounds are more potent at low concentrations and two, provideresidual activity over longer periods of time.

Compounds of this invention and particularly 1-(4-cis-cyclohexylmethylcyclohexyl)-3-methylurea have potential use as riotcontrol agents, dog repellants, deer repellants, rodent repellants andfor contaminating caves or underground tunnels.

PREPARATION The amine and isocyanate are carefully mixed into stirringbenzene. The solution is then refluxed for several hours to insurecompletion of the reaction. Since isocyanates react with water, thereaction system should be kept dry. The benzene is evaporated in vacuumand the residual urea is purified by recrystallization.

Synthesis Route B 3-Alkyl and 3,3-Dialkylureas The preparation of theisocyanates or isothiocyanates in Reaction II is performed by theaddition of the desired amine to a cold toluene solution containing apercent excess of phosgene or thiophosgene. The carbamyl or thiocarbamylcomplex precipitates. The stirring slurry is slowly heated to reflux;reflux is continued until the slurry dissolves and hydrogen chlorideevolution stops. The isocyanates or isothiocyanate is isolated andpurified by distillation.

The urea preparation in Reaction III is similar to that described forReaction I above.

The compounds of this invention'are white crystalline materials whichare easily purified by recrystallization from conventional solvents. Ifdesired, the cis and trans isomers can be separated by chromatographyover silicic acid using chloroform as eluant. The ratio of silicic acidto compound is 50:1.

The amine intermediates are prepared by the following reaction sequence.R is as defined in Formula 1 H N H25 04 RCH -c 0 Na Rcm@mn ketone isisolated from the benzene solution and is purified by distillation.

The Wolff-Kishner reduction (V) is run in 2'(2- ethoxyethoxy)ethanolusing a modification of the procedure given by J. Cason et a]. inOrganic Synthesis, Volumn IV, John Wiley and Sons, N.Y., (1963), P. 510.Once the reactants are mixed, they are heated to reflux for a period of3 to 5 hours. The reflux temperature is generally in the to C. range.After completion of the reflux period, the solution is cooled and pouredinto 3 to 4 volumes of water. The alkylbenzene product is extracted withpentane, and purified by distillation.

The Friedel-Crafts Reaction (VI) is run by mixing approximatelyequimolar quantities of the reactants together in hexane or nitromethaneat less than 5C. The stirring mixture is slowly allowed to warm to roomtemperature, and when hydrogen chloride evolution subsides, the mixtureis refluxed several hours. Water is then added slowly to decompose thecatalyst. A sufficient quantity of water is then added so that all ofthe solids are dissolved. The desired acetophenone deriva tive isisolated from the organic phase and purified by distillation. Gas-liquidchromatography on an F & M Model 500 Gas Chromatograph using a 2 foot XA inch O.D. stainless steel column containing 10 percent Carbowax 20M on60-80 mesh Diatoport T indicates that about 98 percent of theacetophenone is the 1,4-isomer and 2 percent is the 1,2-isomer. The1,2-isomer has the shorter retention time.

The haloform Reaction (VII) is run by slowly adding a cold 5C.) sodiumhypochloride solution to a stirring solution of the acetophenonederivative in methanol. This is a modification of the procedure used byE. E. Royals, J. Am. Chem. Soc., 69, 841 (1947) for the haloformreaction of a-ionone. After the sodium hypochloride solution is added,the mixture is warmed to room temperature, and left standing overnight.The mixture is heated to reflux, and the distillate collected until thepot temperature rises to 95-97C.: most of the methanol is distilled. Thepot is then cooled to room temperature. In those reactions where R is alow molecular weight radical such as butyl, the sodium benzoatederivative remains dissolved; however, when R is a high molecular weightradical such as octyl, the sodium benzoate derivative precipitates as asoapy solid. Sulfur dioxide is bubbled into the alkaline pot concentrateuntil the pH drops below 3. The precipitated benzoic acid derivative iseither filtered and washed with water, or extracted with methylenechloride depending on whether or not the benzoic acid is easilyfilterable or is of a soapy nature. Some of these benzoic acidderivatives can be recrystallized from acetonitrile or pentane, and someare purified merely by trituration with cold pentane.

The catalytic hydrogenation (VIII) is performed at 2 to 3 atmospheres ofhydrogen using platinum oxide as catalyst and glacial acetic acid assolvent. A Parr Hydrogenation Apparatus is suitable for these reactions.This reaction produces a cis to trans isomer mixture of about 2 or 3 tol. The cis and trans designation refers to the relationship of the4-alkyl substituent and carboxylic acid group on the cyclohexane rings.This is illustrated below.

cis

lttlllz trans The Schmidt Reaction (IX) is performed by dissolving thecyclohexane carboxylic acid derivative in a mixture of chloroform andconcentrated sulfuric acid. Sodium azide is then added in small portionsto the stirring mixture at a rate sufficient to keep the reactiontemperature between 35 and 45C. The mixture is stirred at about 45 to50C. until the bubbling nearly stops (1 to 3 hours). The mixture is thentransferred to a separatory funnel, and the lower, gelatinous sulfuricacid layer is slowly dripped into ice. The amine sulfate precipitates asa soapy material which slowly crystallizes. The chloroform should bekept away from the ice water mixture since it makes the work-up muchmore difficult. Those amines which crystallize as the hemisulfates orsulfates are filtered and washed with water. It is convenient to storethe amines as their salts. Those amine salts which fail to crystallizeare converted to the free bases by making the sulfuric acid solutionalkaline and extracting the amine with dichloromethane. The amine isthen purified by distillation. The Schmidt reaction proceeds withoutchanging the cis/trans product ratio.

An alternative synthesis route can be used for these amine intermediatesif the appropriately substituted aniline derivatives are available. Thisroute is illustrated below.

The hydrogenation (X) can be performed on a Parr Hydrogenation Apparatususing platinum oxide as catalyst and glacial acetic acid as solvent. Thecis/trans ratio of the cyclohexylamine products is about 1 :1.

COMPOSITIONS Compounds of this invention can be administered alone, butare generally contained in a composition with an inert diluent non-toxicto animals. The diluent selected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of Formula(1) to aid in dispersion of the active ingredient. Emulsifying agentsthat could be used include alkylaryl polyethoxy alcohols, alkyl andalkyl-aryl polyether alcohols, polyoxyethylene sorbitol or sorbitanfatty esters, polyethylene glycol fatty esters, fatty alkylol amidecondensates, amine salts of fatty alcohol sulfates plus long chainalcohols and oil soluble petroleum sulfonates.

The amount of emulsifying agent in the composition will range from 0.1to percent by weight.

Since the compounds of the present invention would generally beadministered by vapor or spray application, the compositions willcontain a liquid diluent such as water, acetone, hexane, gasoline,kerosene, other hydrocarbon oils, alcohols or other liquids generallyused in pharmaceutical preparations.

The amount of active ingredient in the composition will vary from 0.005percent by weight to 95 percent or even higher. However, the diluentwill generally constitute the major proportion of the composition andthe amount of active ingredient will be less than 50 percent by weight.The exact concentration of the active ingredient will depend on themechanism used for administration and will be easily understood by oneknowledgeable in pharmaceutical application rates.

APPLICATION A quantity of active ingredient sufficient to causeirritation to animal tissue is to 5,000 micrograms per EXAMPLE 1 To asolution of 9 grams (0.15 mole) of methylisocyanate in 200 millilitersof stirring benzene is slowly added 30 grams (0.15 mole) of4-cyclohexylmethylcyclohexylamine. The solution is then refluxed forseveral hours to insure completion of the reaction. The reaction systemis kept dry by the use of a calcium chloride drying tube on top of thereflux condenser. After having refluxed for several hours, the solutionis stripped. The residual solid is recrystallized from acetonitrilegiving pure 1-(4-cyclohexylmethylcyclohexyl )-3-methylurea, m.p. 156-160C.

Anal. Calcd. for C H, N O: C, 71.4; H, 11.2; N,

Found: C, 71.4; H, 11.0; N, 10.9%.

Mice are treated by aerosol exposure to this cis/trans mixture ofl-(4-cyclohexylmethylcyclohexyl)-3- methylurea in the following manner:The compound is administered as an aerosol into a 2.8 liter chamber. Theexposure chamber consists of a 2.8 liter bell jar over a nebullizerinserted through the floor of the chamber. Mice are exposed for fiveminutes to 300.0 micrograms per liter (1,500 Ct). The compound isdissolved in 1.4 ml. of acetone and during a span of 20 seconds thecompound is sprayed up into the chamber. No further air is transferredinto or out of the chamber during the 5-minute exposure.

After this exposure, irritant effects are observed in all mice exposed,but not in controls exposed to 1.4 ml. of acetone alone. Irritanteffects can be described as the presence of one or more of the followingreactive S! s:

hyperemia of the ears, nose and tail b. abnormal gait, including rubbingof the nose on the floor while running about c. blinking d. salivatione. depression f. dyspnea g. hunched posture h. face-pawing.

EXAMPLE 2 A solution of 10 grams of 4-cyclohexylmethycyclohexylamine in30 milliliters of benzene is treated with 5.4 grams ofB-chloroethylisocyanate. The reactants are refluxed for several hours.The benzene is removed in vacuum and the gummy residual solids arerecrystallized from acetonitrile giving pure l-(4-cyclohexylmethylcyclohexyl)-3-(2-chloroethyl)urea: m.p. 1l9l20C.

Anal. Calcd. for C l-l ClN O: C, 63.9; H, 9.7; Cl,

11.8; N, 9.3%. Found: C, 64.2; H, 10.0; Cl, 12.0; N, 9.2%. This compoundis formulated and applied in the manner similar to thel-(4-cyclohexylmethylcyclohexyl)-3-methylurea in Example 1 to providelike results.

EXAMPLES 3 28 The following compounds are made in the manner of the1-(4-cyclohexylmethylcyclohexyl)-3-methylurea of Example 1 bysubstituting like amounts by weight of the appropriate startingmaterials. The compounds are formulated and applied in like manner toprovide like results:

3. l-(4-Cyclohexylmethylcyclohexyl)-3,3-dimethylurea.

4. 1-( 4-n-Butylcyclohexyl)-3-methylurea.

5 1-(4-n-Pentylcyclohexy1)-3-n-butylurea.

6. 1-( 4-Cyclopentylmethylcyclohexyl)-3-ethylthiourea. 7.1-(4-Cyclobutylmethylcyclohexyl)-3,3-diethylurea. 8. l-(4-[2methypentyl]cyclohexyl)-3,3,-di-n-propylurea.

9. 1-( 4-n-Octylcyclohexyl)-3-methylurea.

l0. l-(4-n-Nonylcyclohexyl )urea.

l 1. l-(4-Cyclohexylrnethylcyclohexyl)urea.

1 2. l -(4-n-Hexylcyclohexyl)-3-methylthiourea.

l 3. l-(4-Cyclononylmethylcyclohexyl)-3methylthiourea.

l 4. 1 4-( 4-Ethylheptyl )cyclohexyl )-3-methylurea.

1 5. 1-( 4-n-Heptylcyclohexyl)-3-methyl-3 -butylurea.

1 6. 1-(4-Cycloheptylmethylcyclohexyl )-3- methylthiourea.

l 7. l-(4-n-Butylcyclohexyl )-3-( 3-bromopropyl)urea.

1 8. 1-( 4-n-Butylcyclohexyl)-3-(2-ethoxyethyl)urea.

l 9. l -(4-Cyclohexylmethylcyclohexyl)-3-( 2- cyanoethyl)urea.

20. 1-( 4-Cyclopentylmethylcyclohexyl)-3-( 2- nitroethyl)urea.

21 1-(4-n-Pentylcyclohexyl )-3-( 2-thiomethoxyethyl)urea.

22. l-(4-( 2-[2.2. 1 ]-Bicycloheptylmethyl)cyclohexyl)- 3-methylurea.

23. 1 -(4-( 3-Cyclopentylpropyl)cyclohexyl)-3-ethylurea.

24. l-(4-( 1-Adamantylmethyl)cyclohexyl)-3-methylurea.

25. l-(4-(2-[ 3.2. l ]-Bicyclooctylmethyl)cyclohexyl)-3- methylurea.

26. l-( 4-( l-Homoadamantylmethyl )cyclohexyl )-3- methylurea.

27. l-(4-( 2-[ 3 .2. l ]-Bicycloheptylmethyl)cyclohexyl 3-methylurea.

28. l -(4-(2-[ 3 .3. l ]-Bicyclononylmethyl )Cyclohexyl 3-methylurea.

In each of Examples 1 28 the cis isomer can be isolated bychromatography over silicic acid using chloroform.

EXAMPLE 29 Dogs are exposed tol-(4-cyclohexylmethylcyclohexyl)-3-methylurea spotted on a 6 cm. circleof filter paper. The dogs head is held by an operator, and the driedpaper is shaken 6 to 12 cm. from the muzzle. Within 10-30 seconds thedog salivates, licks his lips, and occasionally face-paws. Generally hestruggles to escape further irritant effects. As little as 10 milligramson paper is sufficient to cause visible discomfort in most dogs.

EXAMPLE 30 A test chamber, comprising a plastic rectangular box of 65liters, is filled with an aerosol spray of l-(4-cyclohexylmethylcyclohexyl)-3-methylurea. The spray is administered 2cm. above an immobilized rabbit, and 3 cm. distant from the end of thenose. The aerosol is aimed directly at the rabbit. Administration ofcompound takes approximately one minute. At 5,000 Ct (5 minutes), therabbit exhibited lacrimation, nasal exudate, face-pawing, and constanthead shaking. After several minutes the eyes becarnse static afterperiods of blinking. Dyspnea continued for two hours after exposure.

I claim:

1. A compound of the formula:

wherein R is selected from the group consisting of alkyl of threethrough eight carbon atoms, cycloalkyl of four through nine carbonatoms, cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl ofseven through 10 carbon atoms, and tricycloalkyl of 10 through 11 carbonatoms;

R and R are separately selected from the group consisting of hydrogen,alkyl of one through four carbon atoms, cyanoalkyl of one through fourcarbon atoms, nitroalkyl of one through four carbon atoms, alkoxyalkylof one through four carbon atoms in the alkoxy and one through fourcarbon atoms in the alkyl and thioalkoxyalkyl of one through four carbonatoms in the thioalkoxy and one through four carbon atoms in the alkyl;and

A is selected from the group consisting of oxygen and sulfur.

2. A compound according to claim 1 which is l-(cis-4-cyclohexylmethylcyclohexyl)-3-methylurea.

3. A compound according to claim 1 which is l-(cis-4-n-butylcyclohexyl)-3-methylurea.

4. A compound according to claim 1 which is l-(cis-4-cyclohexylmethylcyclohexyl)-3-( 2-chloroethyl)urea.

5. A compound according to claim 1 which is l-(cis-4-n-butylcyclohexyl)-3-(2-bromoethyl)urea.

6. A compound according to claim 1 which is l-( cis-4-cyclohexylmethylcyclohexyl)-3-n-propylurea.

7. A compound according to claim 1 which is l-(cis-4-cyclohexylmethylcyclohexyl)-3,3-dimethylurea.

8. A compound according to claim 1 which is l-(cis-4-cyclohexylmethylcyclohexyl)-3-(2-chloropropyl)urea.

2. A compound according to claim 1 which is1-(cis-4-cyclohexylmethylcyclohexyl)-3-methylurea.
 3. A compoundaccording to claim 1 which is 1-(cis-4-n-butylcyclohexyl)-3-methylurea.4. A compound according to claim 1 which is1-(cis-4-cyclohexylmethylcyclohexyl)-3-(2-chloroethyl)urea.
 5. Acompound according to claim 1 which is1-(cis-4-n-butylcyclohexyl)-3-(2-bromoethyl)urea.
 6. A compoundaccording to claim 1 which is1-(cis-4-cyclohexylmethylcyclohexyl)-3-n-propylurea.
 7. A compoundaccording to claim 1 which is1-(cis-4-cyclohexylmethylcyclohexyl)-3,3-dimethylurea.
 8. A compoundaccording to claim 1 which is1-(cis-4-cyclohexylmethylcyclohexyl)-3-(2-chloropropyl)urea.